This is the A1 amended submission of a third competitive renewal of a translational P01 whose continuing goal is to develop and test novel therapies for malignant pleural mesothelioma (MPM) within the structure of a highly interactive multi-disciplinary group that moves from bench-to-bedside and back again. The overall hypothesis is that immuno- and immuno-gene therapy can be used to treat MPM successfully. In the preceding funding period, the Program conducted preclinical work that led to clinical trials using direct intrapleural injection of an adenovirus expressing a type I interferon (Ad.IFN), ultimately leading to a Phase 2 trial, and developed the technology to allow initiation of a clinicl trial using adoptive transfer of genetically modified T-cells that react against the MPM antigen mesothelin. In this proposal, the focus will be on completion of the Phase 2 trial and on moving adoptive T-cell transfer trials forward. The renewal is organized into three projects supported by three Cores. Project 1 (Clinical Trials) will conduct a Phase 2 clinical trial using a combination f intrapleural Ad.IFN and a COX-2 inhibitor with first- or second-line chemotherapy. It will also begin clinical trials using adoptive transfer of gene-modified T-cells. Project 2 (Preclinical Studies) and Project 3 (Genetically Modified T cells) will continue to develop and optimize adoptive immunotherapy for mesothelioma using genetically modified lymphocytes expressing chimeric antigen receptors (CARs). Project 2 will focus on increasing trafficking of T cells into tumors, optimizing combination with chemotherapy, and enhancing T cell function by altering the tumor microenvironment and preventing T cell inactivation. Project 3 will focus on using RNA engineering to create RNA CARs, testing the antitumor activity of combinatorial CAR-based immunotherapy, and conducting experiments using patient material from Project 1 to assess the activity of the transfused T cells. Core A will supply administrative infrastructure. Core B will provide support as the Tissue Acquisition, Sample Processing, and Pathology Core. Core C will provide biostatistical and data management services. The goal of this P01 is to alter the treatment paradigm for MPM and advance the entire field of adoptive T cell transfer.